A Study MLN2480 in Combination With MLN0128 or Alisertib, or Paclitaxel, or Cetuximab, or Irinotecan in Adult Participants With Advanced Nonhematologic Malignancies

Phase 1

Completed

• Conditions: Advanced Nonhematologic Malignancies
• Interventions: Drug: MLN2480; Drug: MLN0128; Drug: Alisertib; Drug: Paclitaxel; Drug: Cetuximab; Drug: Irinotecan

• Registration Number: NCT02327169
• Lead Sponsor: Millennium Pharmaceuticals, Inc.

Brief Summary

The primary purpose of this study is to determine the safety profile and the maximum tolerated doses (MTDs)/ potential recommended phase 2 doses (RP2Ds) of the combination treatments of MLN2480 + MLN0128, MLN2480 + alisertib, MLN2480 + paclitaxel, MLN2480 + cetuximab, and MLN2480 + irinotecan in participants with advanced nonhematologic malignancies.

Detailed Description

The drug being tested in this study is called MLN2480 (TAK-580). MLN2480 was tested to evaluate side effects and determine the maximum tolerated dose (MTD) and recommended dose for future studies when administered in combination with five other medications. This study was to assess the safety of MLN2480 as well as how it is processed by the body in participants with solid nonhematologic malignancies who have failed standard therapies.

The study was to be conducted in two phases, the dose escalation phase and the dose expansion phase. A total of 71 participants were enrolled in the escalation phase. Participants in this phase were assigned to one of the five treatment groups:

* MLN2480 + MLN0128

* MLN2480 + Alisertib

* MLN2480 + Paclitaxel

* MLN2480 + Cetuximab

* MLN2480 + Irinotecan

Once the MTD for each combination treatment arm was established in the escalation phase, one or more of the combination treatments will be selected for the expansion phase. A total of 10 participants were enrolled in the expansion phase.

This multi-centre trial was be conducted worldwide. The overall time to participate in this study is approximately 14 months. Participants made multiple visits to the clinic including an end of study visit 30 days after last dose of study drug for a follow-up assessment.

Study Timeline

• Study First Submitted: 2014-12-23
• Study First Submitted QC: 2014-12-23
• Study First Posted: 2014-12-30
• Study Start: 2015-01-14
• Primary Completion: 2018-07-02
• Study Completion: 2018-07-02
• Results First Submitted: 2019-06-26
• Status Verified: 2020-02
• Results First Submitted QC: 2020-02-11
• Last Update Submitted: 2020-02-11
• Results First Posted: 2020-02-25
• Last Update Posted: 2020-02-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 81

Inclusion Criteria

All Treatment Arms:

1. Male or female participants 18 years or older.

2. Participants who, in the opinion of the treating physician, have failed standard therapies and for whom a phase 1 trial is an appropriate option.

3. Radiographically or clinically evaluable tumor. For expansion phase: Tumors must be measurable and of the protocol specified genetic mutational status, where applicable.

4. Recovered (ie, less than or equal to [<=] Grade 1 toxicity) from adverse effects (except alopecia) of prior therapy.

5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

6. Expected survival time of at least 3 months in the opinion of the investigator.

7. Block of banked tumor tissue and/or greater than or equal to (>=) 10 unstained slides. Participants who satisfy all other eligibility criteria but do not have banked tissue/slides may be asked to consent to baseline biopsy.

8. Suitable vein access for the study-required blood sampling.

9. Thyroid function tests consistent with stable thyroid function. Note: Participants on a stable dose of thyroid replacement therapy for a suggested minimum of 12 weeks before Cycle 1, Day 1 are eligible.

10. Left ventricular ejection fraction (LVEF) of 50 percent (%) or greater, as measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA), within 28 days before the first dose of MLN2480

11. Female participants who are post-menopausal for at least 1 year, surgically sterile, or agree to practice 2 effective methods of contraception through 120 days (4 months) after the last dose of study drug for participants in Arms 1, 2, and 5, and through 6 months for participants in Arms 3 and 4, or agree to practice true abstinence.

12. Male participants who, even if surgically sterilized, agree to practice effective barrier contraception through 120 days (4 months) after the last dose of study drug for participants in Arms 1, 2, and 5, and through 6 months for participants in Arms 3, and 4, or agree to practice true abstinence.

13. Additional inclusion criteria for arm 3 expansion only (MLN2480 + paclitaxel):

    a. Participants with Kirsten rat sarcoma viral oncogene homolog (KRAS) exon 2 or BRAF non-V600 mutation-positive non-small cell lung cancer (NSCLC) who have received a minimum of 1 but not more than 2 prior cytotoxic-approved regimens.

14. Additional inclusion criteria for arms 4 and 5 expansion only (MLN2480 + cetuximab; MLN2480 + irinotecan):

    1. Participants with CRC who have received a minimum of 1 but not more than 2 prior cytotoxic-approved regimens.

Exclusion Criteria

All treatment arms:

1. Female participants who are pregnant or currently breastfeeding.

2. History of any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with safe protocol completion.

3. History of uncontrolled brain metastasis unless: previously treated with surgery, whole-brain radiation, or stereotactic radiosurgery; stable disease for >= 60 days without steroid use (or stable steroid dose established for >= 28 days before the first dose of MLN2480).

4. Ongoing seizure disorder or a requirement for antiepileptics.

5. Recent prior therapies, including: chemotherapy and hormonal therapy <= 4 weeks or 4 half lives, whichever occurs first, before administration of study drug; immunotherapy/monoclonal antibody use <= 4 weeks before administration of MLN2480; or radiation therapy <= 3 weeks before administration of study drug.

6. Chronic therapeutic corticosteroid use with the exception of replacement therapy for adrenal insufficiency or corticosteroid inhalers.

7. Known history of human immunodeficiency virus infection, hepatitis B, or hepatitis C; Prior allogeneic bone marrow or organ transplantation, or active condition of chronic immune suppression is not allowed.

8. Concomitant use, or administration <= 14 days before first dose of study drug(s), of clinically significant enzyme inducers.

9. Treatment with gemfibrozil (strong Cytochrome P4502C8 [CYP2C8] inhibitor) within 14 days before the first dose of MLN2480.

10. History of or current illicit drug use, drug abuse, or alcohol abuse.

11. Major surgery within 14 days before the first dose of study drug.

12. Inability to comply with study requirements.

13. Other unspecified reasons that, in the opinion of the investigator or Millennium, make the participant unsuitable for enrollment.

14. Additional exclusion criteria for arms 3, 5, and 6 expansion only (MLN2480 + paclitaxel; MLN2480 + irinotecan; MLN2480 monotherapy):

    a. Prior treatment with rapidly accelerated fibrosarcoma (RAF), extracellular signal-regulated kinases (MEK), or other inhibitors of the mitogen-activated protein kinase (MAPK) pathway.

15. Additional exclusion criteria for arm 2 only (MLN2480 + alisertib):

    a. History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease.

16. Additional exclusion criteria for arm 3 only (MLN2480 + paclitaxel):

    a. Known hypersensitivity to paclitaxel, or its components or other drugs formulated in Cremophor® EL (polyoxyethylated castor oil).

17. Additional exclusion criteria for arm 5 only (MLN2480 + irinotecan):

    1. Use of strong or moderate Cytochrome P4503A (CYP3A) inhibitors <= days of the first dose of irinotecan.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
MLN2480 + MLN0128	MLN2480	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
MLN2480 + MLN0128	MLN0128	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
MLN2480 + Alisertib	Alisertib	Dose Escalation Phase: MLN2480 100-200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30-40 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
MLN2480 + Paclitaxel	MLN2480	Dose Escalation Phase: MLN2480 100-200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m\^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles or MLN2480 400-600 mg tablets, orally, QW on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m\^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
MLN2480 600 mg + Paclitaxel 80 mg (Dose Expansion Phase)	MLN2480	Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg, capsules, orally, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
MLN2480 + Alisertib	MLN2480	Dose Escalation Phase: MLN2480 100-200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30-40 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
MLN2480 + Cetuximab	MLN2480	Dose Escalation Phase: MLN2480 400-600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m\^2 (cycle 1 Day 1), then at 250 mg/m\^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care.
ML2480 + Irinotecan	MLN2480	Dose Escalation Phase: MLN2480 400-600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m\^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care.
MLN2480 + Paclitaxel	Paclitaxel	Dose Escalation Phase: MLN2480 100-200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m\^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles or MLN2480 400-600 mg tablets, orally, QW on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m\^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
MLN2480 + Cetuximab	Cetuximab	Dose Escalation Phase: MLN2480 400-600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m\^2 (cycle 1 Day 1), then at 250 mg/m\^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care.
ML2480 + Irinotecan	Irinotecan	Dose Escalation Phase: MLN2480 400-600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m\^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months)	An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An SAE means any untoward medical occurrence that at any dose results in death, is life-threatening, requires in patient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event.
Number of Participants With Dose-Limiting Toxicities (DLTs)	From Day 1, Cycle 1 through 30 days after the last dose in Cycle 1 (up to 8 weeks)	DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 and included: any drug-related hematologic toxicity ≥Grade 4 with the exception of Grade 4 neutropenia \<7 days duration; Grade 3 or 4 neutropenia with fever \>38.5 degrees Celsius and/or infection or neutropenia requiring colony-stimulating factor OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions: Grade 3 nausea, vomiting, diarrhea, and dehydration occurring in a setting of inadequate treatment; inadequately treated hypersensitivity reactions; Grade 3 elevated transaminases or urine electrolyte abnormality ≤1 week in duration; Grade 3 serum electrolyte abnormality ≤72 hours in duration. DLTs also included: drug-related adverse experience that lead to a dose modification; unresolved drug-related toxicity resulted in delay in initiation of Cycle 2.
Maximum Tolerated Dose (MTD) for MLN2480	Day 1, Cycle 1 up to 28 days
Recommended Phase 2 Dose (RP2D) of MLN2480	Day 1, Cycle 1 up to 28 days

Secondary Outcome Measures

Name	Time	Method
Cmax : Maximum Observed Plasma Concentration for MLN2480	Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Cmax: Maximum Observed Plasma Concentration for MLN0128	Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Cmax: Maximum Observed Plasma Concentration for Alisertib	Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN2480	Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128	Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib	Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN2480	Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN0128	Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Alisertib	Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Cmax: Maximum Observed Plasma Concentration for Paclitaxel	Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel	Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel	Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Terminal Elimination Half-life (T1/2) for Paclitaxel	Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST)	Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Up to 13 months)	ORR was defined as the percentage of participants with complete response (CR) or partial response (PR) using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.
Duration of Response	From first documented response until disease progression (Up to 13 months)	Duration of Response (DOR) was defined as the time in months from the first documented CR or PR per RECIST v. 1.1 to disease recurrence or disease progression (PD) whichever occurs first.
Time to Response	From date of enrollment to the date of the first documentation of a confirmed response (Up to 13 months)	Time to response was defined as the time in months from the date of first dose of study treatment to the date of the first documentation of a PR or better response.
Progression Free Survival (PFS)	Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Approximately up to 13 months)	PFS is defined as the time in months from the date of first study drug administration to the date of first documented PD or death due to any cause. PD was based on response evaluation criteria in solid tumors (RECIST V1.1), defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Trial Locations

Locations (14)

Fox Chase Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Massachusetts General Hospital Cancer Center; 🇺🇸 Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center; 🇺🇸 Boston, Massachusetts, United States

The University of Texas MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Churchill Hospital; 🇬🇧 Oxford, Oxfordshire, United Kingdom

Institut Bergonie; 🇫🇷 Bordeaux cedex, Gironde, France

Hospital Clinico Universitario Virgen de la Victoria; 🇪🇸 Malaga, Spain

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Sarah Cannon Research Institure UK; 🇬🇧 London, Greater London, United Kingdom

The Chrisie; 🇬🇧 Manchester, Greater Manchester, United Kingdom

Institut Claudius Regaud-Oncopole; 🇫🇷 Toulouse cedex 09, Haute Garonne, France

START Madrid. Fundacion Jimenez Diaz; 🇪🇸 Madrid, Spain

Hospital Universitari Vall d'Hebron; 🇪🇸 Barcelona, Spain

Institut Gustave Roussy; 🇫🇷 Villejuif cedex, Val De Marne, France